In recent years, the emergence and spread of multi-drug resistant pathogens have become a serious problem in treating infectious disease. See Livermore, D. Nature Reviews Microbiology 2004, 2, 73-78; Tenover, F. C. Pharmacy world & science, Sep. 22, 1995, 17, 149-151. As a result of this urgent health concern, there is a need to identify new antibiotics with unexploited modes of action.
The chemical and medical literature describes a myriad of compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. In particular, antibacterials include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds. They may be classified as aminoglycosides, ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d Edition (1981).
The mechanisms of action of these antibacterials vary. However they can generally be classified as functioning in one of the following ways. Antibacterials may function by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. On the other hand, quinolones act by inhibiting synthesis of bacterial DNA, thus preventing the bacteria from replicating.
Not surprisingly, the pharmacological characteristics of antibacterials and other antimicrobials, as well as their suitability for a specific clinical use, varies considerably. For example, the classes of antimicrobials (and members within a class) may vary in their relative efficacy against different types of microorganisms and their susceptibility to development of microbial resistance. These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial (or other antimicrobial) in any given clinical situation can be a complicated analysis of many factors, including the type of organism involved, the desired method of administration, and the location of the infection to be treated.
The pharmaceutical literature is replete with attempts to develop improved antimicrobials (i.e., compounds that have a broader scope of activity, greater potency, improved pharmacology, and/or less susceptibility to resistance development.) One group of antimicrobials recently developed for clinical use is the quinolones. These compounds include, for example, nalidixic acid, difloxacin, enoxacin, fleroxacin, norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin, and pefloxacin. See, C. Marchbanks and M. Dudley, “New Fluoroquinolones,@ 7 Hospital Therapy 18 (1988); P. Shah, “Quinolones,@ 31 Prog. Drug Res. 243 (1987); Quinolones—Their Future in Clinical Practice, (A. Percival, Editor, Royal Society of Medical Services, 1986); and M. Parry, “Pharmacology and Clinical Uses of Quinolone Antibiotics,@ 116 Medical Times 39 (1988).
However, many such attempts to produce improved antimicrobials have produced equivocal results. For example, the quinolones often show reduced effectiveness against certain clinically important pathogens, such as gram positive bacteria and/or anaerobic bacteria. The quinolones also have limited water solubility limiting their bioavailability and suitability for parenteral dosing. They may also produce adverse side effects, such as gastrointestinal disturbance and central nervous system effects such as convulsions. Accordingly there remains a need for new effective antimicrobial compounds.